Nadia Hindi

Systemic therapy for selected skull base sarcomas: Chondrosarcoma, chordoma, giant cell tumour and solitary fibrous tumour/hemangiopericytoma

This review highlights the data currently available on the activity of systemic therapy in chondrosarcoma, chordoma, giant cell tumour of the bone (GCTB) and solitary fibrous tumour, i.e., four rare sarcomas amongst mesenchymal malignancy arising from the skull base.

Activity of Pazopanib and Trabectedin in Advanced Alveolar Soft Part Sarcoma

BACKGROUND Alveolar soft part sarcoma (ASPS) is an exceedingly rare and orphan disease, without active drugs approved in the front line. Pazopanib and trabectedin are licensed for sarcoma treatment from second-line, but very little and contradictory data are available on their activity in ASPS. Lacking ongoing and/or planned clinical trials, we conducted a multi-institutional study involving the reference sites for sarcoma in Europe, U.S., and Japan, within the World Sarcoma Network, to investigate the efficacy of pazopanib and trabectedin. MATERIALS AND METHODS From May 2007, 14 of the 27 centers that were asked to retrospectively review their databases had identified 44 advanced ASPS patients treated with pazopanib and/or trabectedin. Response was evaluated by Response Evaluation Criteria in Solid Tumors 1.1. Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method. RESULTS Among 30 patients who received pazopanib, 18 were pretreated (13 with other antiangiogenics). Response was evaluable in 29/30 patients. Best responses were 1 complete response, 7 partial response (PR), 17 stable disease (SD), and 4 progressions. At a 19-month median follow-up, median PFS was 13.6 months (range: 1.6-32.2+), with 59% of patients progression-free at 1 year. Median OS was not reached.Among 23 patients treated with trabectedin, all were pretreated and evaluable for response. Best responses were 1 PR, 13 SD, and 9 progressions. At a 27-month median follow-up, median PFS was 3.7 months (range: 0.7-109), with 13% of patients progression-free at 1 year. Median OS was 9.1 months. CONCLUSION The value of pazopanib in advanced ASPS is confirmed, with durable responses, whereas the value of trabectedin appears limited. These results are relevant to defining the best approach to advanced ASPS. IMPLICATIONS FOR PRACTICE This retrospective study, conducted among the world reference centers for treatment of sarcoma, confirms the value of pazopanib in patients with advanced alveolar soft part sarcoma (ASPS), with dimensional and durable responses, whereas trabectedin shows a limited activity. Alveolar soft part sarcoma is resistant to conventional cytotoxic chemotherapy. Pazopanib and trabectedin are licensed for treatment of sarcoma from second line; in the lack of prospective clinical trials, these results are relevant to defining ASPS best management and strongly support initiatives aimed at obtaining the approval of pazopanib in the front line of the disease.

Gemcitabine plus sirolimus for relapsed and progressing osteosarcoma patients after standard chemotherapy: a multicenter, single-arm phase II trial of Spanish Group for Research on Sarcoma (GEIS).

Background Patients with relapsed unresectable osteosarcoma represents an unmet need, so active and safe systemic treatments are required. Fas cell surface death receptor and mammalian target of rapamycin pathways are implicated in progressing osteosarcoma, and we had preclinical and clinical experience with a scheme that targets both pathways. Therefore, we designed a phase II trial with gemcitabine plus rapamycin, to determine the efficacy and safety, in this subset of patients. Patients and methods A multicenter, single-arm phase II trial was sponsored by the Spanish Group for Research on Sarcoma. Osteosarcoma patients, relapsed or progressing after standard chemotherapy and unsuitable for metastasectomy received gemcitabine and rapamycin p.o. 5 mg/day except for the same day of gemcitabine administration, and the day before. The main end point was 4-month progression-free survival rate (PFSR), with the assumption that rates higher than 40% would be considered as an active regimen. Translational research aimed to correlate biomarkers with the clinical outcome. Results Thirty-five patients were enrolled and received at least one cycle. PFSR at 4 months was 44%, and after central radiologic assessment, 2 partial responses and 14 stabilizations (48.5%) were reported from 33 assessable patients. The most frequent grade 3-4 adverse events were: neutropenia (37%), thrombocytopenia (20%), anemia (23%), and fatigue (15%); however, only three patients had febrile neutropenia. Positive protein expression of RRM1 significantly correlated with worse PFS and overall survival, while positivity of P-ERK1/2 was correlated with significant better overall survival. Conclusion Gemcitabine plus sirolimus exhibits satisfactory antitumor activity and safety in this osteosarcoma population, exceeding the prespecified 40% of 4-month PFSR. The significant correlation of biomarkers with clinical outcome encourages further prospective investigation.

Targeted treatments of sarcomas and connective tumors beside gastrointestinal stromal tumor.

Purpose of review Sarcoma is a heterogeneous group of malignancies historically treated with classic cytotoxic chemotherapy. This review updates the recent advances in targeted therapies in soft-tissue sarcoma, bone sarcoma and other connective diseases with local aggressiveness. Recent findings Platelet-derived growth factor receptor (PDGFR) inhibitors, antiangiogenics, cell cycle inhibitors and immunomodulatory agents are the main targeted therapies in development in sarcoma. PDGFR&agr; inhibitor olaratumab is being evaluated in a phase III trial in combination with doxorubicin against doxorubicin in monotherapy and, in case of positive results, it could change the standard in the first-line setting. Immunotherapy is still in the early phases of development, although some data in synovial sarcoma are promising. Targeted agents are also in development in other mesenchymal neoplasms, such as the inhibitor of colony stimulating factor 1 receptor for pigmented villonodular synovitis. Summary Several targeted therapies are in development in sarcoma and could be added to the therapeutic armamentarium in the near future. However, predictive factors still need to be identified to better select the target population of these new drugs.

Response of conventional chondrosarcoma to gemcitabine alone: a case report

Conventional skeletal chondrosarcoma is a bone neoplasm, which is poorly sensitive to anthracyclines-based chemotherapy. We report on an 18-month-long tumour response to gemcitabine as single agent in a young patient with an advanced secondary peripheral conventional chondrosarcoma, previously treated unsuccessfully with anthracyclines, ifosfamide, platinum, etoposide.

Current and future systemic treatment options for advanced soft-tissue sarcoma beyond anthracyclines and ifosfamide

Sarcomas are rare, life-threatening, malignant tumors. Surgery is the cornerstone of therapy in the localized setting. About one-third of patients develop distant metastasis. In the metastatic setting, systemic therapy is the mainstay of treatment, and several second-line options are available, proving a modest survival increase for these patients. Trabectedin is an active drug with several described mechanisms of action. Although the objective response rate is low, about one-third of patients achieve disease stabilizations and a prolonged disease control. Interestingly, it has no accumulative toxicities. Pazopanib is the only targeted therapy approved for soft-tissue sarcoma (STS), with the exception of adipocytic sarcoma. Eribulin represents a recently approved therapeutic option for liposarcoma. Other drugs such as gemcitabine combinations, dacarbazine, and taxanes have also shown activity in second lines in advanced STS. The selection should be based on histologic subtype, patient characteristics, and toxicity profile among other factors. This review will summarize clinical development of the current and future therapeutic options for this heterogeneous group of diseases.

Gene expression analyses determine two different subpopulations in KIT-negative GIST-like (KNGL) patients

Introduction There are limited findings available on KIT-negative GIST-like (KNGL) population. Also, KIT expression may be post-transcriptionally regulated by miRNA221 and miRNA222. Hence, the aim of this study is to characterize KNGL population, by differential gene expression, and to analyze miRNA221/222 expression and their prognostic value in KNGL patients. Methods KIT, PDGFRA, DOG1, IGF1R, MIR221 and MIR222 expression levels were determined by qRT-PCR. We also analyzed KIT and PDGFRA mutations, DOG1 expression, by immunohistochemistry, along with clinical and pathological data. Disease-free survival (DFS) and overall survival (OS) differences were calculated using Log-rank test. Results Hierarchical cluster analyses from gene expression data identified two groups: group I had KIT, DOG1 and PDGFRA overexpression and IGF1R underexpression and group II had overexpression of IGF1R and low expression of KIT, DOG1 and PDGFRA. Group II had a significant worse OS (p = 0.013) in all the series, and showed a tendency for worse OS (p = 0.11), when analyzed only the localized cases. MiRNA222 expression was significantly lower in a control subset of KIT-positive GIST (p < 0.001). OS was significantly worse in KNGL cases with higher expression of MIR221 (p = 0.028) or MIR222 (p = 0.014). Conclusions We identified two distinct KNGL subsets, with a different prognostic value. Increased levels of miRNA221/222, which are associated with worse OS, could explain the absence of KIT protein expression of most KNGL tumors.

Report from the 4th European Bone Sarcoma Networking meeting: focus on osteosarcoma

This report summarizes the proceedings of the 4th European Bone Sarcoma Networking Meeting, held in London, England, on 21 June 2017. The meeting brought together scientific and clinical researchers and representatives from sarcoma charities from 19 countries representing five networks across Europe, to present and discuss new developments on bone sarcoma. In view of the challenges is poses, the meeting focussed primarily on osteosarcoma with presentations on developments in our understanding of osteosarcoma genetics and immunology as well as results from preclinical investigations and discussion of recent and ongoing clinical trials. These include studies examining the efficacy of multi-targeted tyrosine kinase inhibitors and checkpoint inhibitors, as well as those with molecular profiling to stratify patients for specific therapies. Discussion was centred on generation of new hypotheses for collaborative biological and clinical investigations, the ultimate goal being to improve therapy and outcome in patients with bone sarcomas.